Inflammatory bowel disease (IBD) is a general term that refers to conditions characterized by chronic inflammation of the tissues that comprise the digestive tract. Symptoms associated with IBDs may include abdominal pain and cramps, diarrhea, weight loss and intestinal or rectal bleeding. Up to one million Americans suffer from either of these two diseases, with roughly equal numbers for each. The causes of these diseases are unknown.
The two most common forms of IBD are ulcerative colitis and Crohn's disease. Less common forms of IBD include collagenous and lymphocytic colitis and colitis associated with enteric microbial pathogens. Ulcerative colitis is an inflammatory disorder of the large bowel (colon and rectum) characterized by inflammation and ulceration of the innermost lining of the colon. Symptoms include abdominal pain, abdominal cramping, decreased appetite and weight loss, tenesmus, and diarrhea, which may be accompanied by rectal bleeding. Inflammation associated with ulcerative colitis can involve the entire length of the colon but is usually greatest in the rectum and may extend continuously for varying distances along the colon, occurring most typically in a proximal to distal pattern of inflammation.
Crohn's disease is another type of inflammatory bowel disease. Crohn's disease can affect any portion of the digestive tract, but is most commonly seen in the distal portion of the small intestine. Approximately 40% of Crohn's disease patients have inflammatory disease localized in the ileocecal region, 30-35% of the patients have disease in the proximal small bowel and the stomach, and about 25% of patients have disease localized in the large bowel. Unlike ulcerative colitis, Crohn's disease can exhibit areas of normal intestine between regions of affected intestine, termed “skip” areas. Also, Crohn's disease is distinguishable from ulcerative colitis in that ulcerative colitis affects only the innermost lining of the colon, while in Crohn's disease the entire thickness of the bowel wall is involved, often resulting in fistulae.
Treatment of IBDs usually involves administration of aminosalicylates (i.e., 5-aminosalicylic acid or sulfasalazine); immunomodulatory compounds (i.e., azathioprine, cyclosporine or 6-mercaptopurine); steroid drugs (i.e., prednisone, methylprenisolone, or budesonide); or monoclonal antibodies directed to cytokines, such as TNF-alpha, and other inflammatory mediators. Anti-TNF alpha antibodies have been used successfully to treat steroid-refractory fistulating Crohn's disease. Aminosalicylates are used to treat mild to moderate cases of IBD and are usually the first line therapy for patients initially presenting with Crohn's disease. In addition, immunomodulatory drugs such as methotrexate or azathioprine are routinely given to patients who fail to respond to aminosalicylates. However, the immunomodulatory drugs may take up to three months to begin to take effect and can also result in increased risk of neoplastic diseases. In severe cases, surgery to remove the affected areas of the colon or bowel may be required. Surgery is inevitably required to treat chronic Crohn's disease of decades duration.
The treatment of choice for moderate to severe ulcerative colitis and Crohn's disease is administration of steroid drugs, which are potent anti-inflammatory agents. Steroid drugs may be administered orally, intravenously, via an enema or via a suppository, depending on the location, severity and extent of the disease. In most instances, steroid drugs are given orally and occasionally parenterally. Steroids are typically given to ablate the initial symptoms of inflammation and are rarely given repetitively over long term because of the side effects. Oral administration is most preferred for its ease and effectiveness. The steroid drugs used routinely in treating IBD are prednisone, methylprednisone or prednisolone. However, the use of such steroids by oral, topical or injection routes of administration results in high levels of the steroid drug in the systemic circulation. Long term used of these drugs beyond daily doses over a period of several weeks can result in a variety of undesirable side effects, including weight gain, thinning of the epidermis, moon face, acne, facial hair, hypertension, mood swings, and increased susceptibility to infection, and diminishment of the hypothalamic-pituitary-adrenal (HPA) axis.
Steroid drugs may retain potent activity when administered topically, a characteristic which has been successfully utilized in the treatment of asthma and certain skin disorders. However, since systemic absorption of steroid drugs occurs even when the drugs are administered topically, the same undesirable side effects are produced. Therefore, there remains a need for a method to treat IBDs, such as ulcerative colitis and Crohn's disease, that can take advantage of the powerful anti-inflammatory properties of steroid drugs without producing the associated undesirable side effects.
Steroids with topical, but moderate systemic activity have been characterized and have been used in the treatment of IBD. A variety of steroid analogues has been developed over the last several decades. These steroids characteristically have high activity in vitro in binding to steroid receptors, but in vivo are rapidly metabolized in the liver to inactive or less active metabolites. High degree of first pass metabolism in the liver largely bypasses the undesirable toxic side effects of steroid administration. To be effective in treatment of IBD, a topically active steroid must be formulated in such a manner to reach the affected inflamed portions of the gastrointestinal tract. This has been accomplished by producing galenic formulations of topical steroids that can be administered as enemas to treat ulcerative colitis or controlled release formulations that can be taken orally to treat inflammation in the small or large intestine. Controlled release formulations are typically designed to release drug conditionally from a polymer matrix, for instance, when encountering a change in pH of the milieu, or by simple erosion of the matrix and diffusion of the drug from the matrix. For example, U.S. Pat. No. 5,643,602 describes formulation of budesonide and other steroids analogues coating a core consisting of a non-pareil seed and where the core is further surrounded by a polymeric coating that dissolved at high pH found in the ileocecal region of the intestine. The formulations described in U.S. Pat. No. 5,643,602 are thus designed to release topical steroid slowly in the small intestine and consequently little topical drug is available in the proximal segment of the small intestine. U.S. Pat. No. 6,096,731 further discloses prophylaxis of liver and cellular damage arising from graft versus host disease using beclomethasone formulated in gelcapsules and enteric coated gel capsules. Therefore, what is needed in the treatment of Crohn's disease is formulations of topical steroids that effectively treat both proximal and small bowel inflammation and inflammation in the stomach. Additionally, what is need is a formulation of a topical steroid that will reach sufficient local concentration in the distal small bowel and the colon for treatment of colitis.